The recently identified human 5-hydroxytryptamine-7 (5-HT7) receptor subtype has been cloned, and the extensive distribution of its mRNA has been reported. Highest levels of 5-HT7 receptor mRNA have been observed in the hypothalamus, thalamus, brainstem and hippocampus, while lower levels have been found in the cerebral cortex, striatum, olfactory bulb and olfactory tubercle. The presence of 5-HT7 mRNA is not limited to the brain, it has also been found in peripheral tissues, namely spleen, stomach, ileum, intestine, coronary artery, descending colon, smooth muscle cells and heart.
Distribution and pharmacological studies have suggested that the 5-HT7 receptor may be involved in the vasodilation of blood vessels, and therefore may play a role in cardiovascular indications. 5-HT7 receptors also play a role in the control of circadian rhythms of spontaneous electrical activity in the suprachiasmatic nucleus. The high affinity of a number of antipsychotic agents for the 5-HT7 receptor suggests that this receptor may help mediate the therapeutic actions of these compounds.
Octahydro-pyrrolo-isoquinoline derivatives, as antipsychotic neuroleptic agents are disclosed in EP 10661 having the formula: 
where R2 is hydrogen, alkyl, cycloalkyl, alkenyl, acyl, aryl or aralkyl.
Ancilated indole derivatives as antiphlogistics are disclosed in DE 77-2740836 having the formula: 
wherein:
R is phenyl or heterocycle,
R1, R2 are alkyl, carboxyalkyl, phenyl, and
R3, R4 is a 5 or 6 membered ring optionally containing 1-3, 5, O or N atoms.
A series of novel 3-(2-aminoethyl)-pyrrolo[2,3-g]isoquinolin-5-one derivatives are claimed that are effective pharmaceuticals for the treatment of anxiety, depression and related CNS disorders and other conditions such as schizophrenia, sleep disorders, including instances of circadian rhythm, the treatment of alcohol and drug withdrawal and sexual dysfunction.
This invention relates to novel 3-(2-aminoethyl)-pyrrolo[2,3-g]isoquinolin-5-one derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in therapy. The compounds are believed to be useful for the treatment of CNS disorders such as anxiety, depression and related CNS conditions and other conditions such as schizophrenia, sleep disorders, including instances of circadian rhythm, migraine headaches, the treatment of alcohol and drug withdrawal and sexual dysfunction by virtue of their ability to bind to the 5-HT7 receptor subtype. The compounds of the present invention may also find utility in the treatment of cardiovascular and septic shock, hypotension, renal disorders, diarrhea and spastic colon.
Compounds of the present invention are represented by the general formula 
wherein:
R1 is hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, heterocycloalkyl of 3 to 8 members, alkylcycloalkyl of 4 to 9 carbon atoms, alkylheterocycloalkyl of 4 to 9 members or (CH2)mAr or (CH2)mHet;
R2 is hydrogen, alkyl of 1 to 8 carbon atoms, (CH2)nAr or (CH2)nHet;
R3 is hydrogen, alkyl of 1 to 8 carbon atoms, alkylcycloalkyl of 4 to 9 carbon atoms, alkylheterocycloalkyl of 4 to 9 members, (CH2)nAr or (CH2)nHet;
R4 is hydrogen or alkyl of 1 to 8 carbon atoms;
R is hydrogen or alkyl of 1 to 4 carbon atoms;
X is [(CHxe2x95x90CH)R]n, (CH2)n, or [(Cxe2x89xa1C)R]n, CHR(CH2)n, CR2(CH2)n;
a dashed line represents an optional double bond;
m is an integer selected from 1 or 2; and
n is an integer selected from 0, 1 or 2, or a pharmaceutically acceptable salt thereof.
In some preferred aspects of the present invention R1 is hydrogen, alkyl of 1 to 8 carbon atoms, alkylcycloalkyl of 4 to 9 carbon atoms, alkylheterocycloalkyl of 4 to 9 members, (CH2)nAr or (CH2)nHet.
In other embodiments of the present invention R2 is hydrogen or alkyl of 1 to 8 carbon atoms.
X is preferably (CH2)n, and the optional double bond is preferably absent.
R3 and R4 are preferably hydrogen or alkyl.
Alkyl refers to straight or branched chain alkyl.
Cycloalkyl refers to a saturated ring of 3 to 8 carbon atoms and preferably 5 to 6 carbon atoms such as cyclopentyl and cyclohexyl.
Heterocycloalkyl refers to a saturated ring of 3 to 8 carbon atoms having 1 or 2 heteroatoms selected from N, O and S. Preferably, heterocycloalkyl refers to 5 or 6 membered rings having at least one nitrogen heteroatom such as piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, morpholinyl, thiomorpholinyl, and pyrazolidinyl.
Ar is aryl and preferably is phenyl or naphthyl which may optionally be substituted by one or more groups selected from flourine, chlorine, bromine, iodine, hydroxy, alkyl of 1 to 6 carbon atoms, trifluoromethyl, cyano and amino.
Het refers to heteroaryl and refers to a monocyclic 5 or 6 membered heteroaryl group or a 9 or 10 membered bicyclic heteroaryl group. Preferred heteroaryls have 1 or 2 heteroatoms selected from N, O and S, and, when 2 heteroatoms are present, it is preferred that at least one heteroatom is nitrogen. Exemplary monocyclic heteroaryl groups include pyridinyl, pyriminidinyl, pyrazinyl, furyl, thienyl, pyrrolyl, indolyl. Exemplary bicyclic heteraryl groups include benzodioxanyl or quinolyl. Heteroaryl groups may optionally be substituted with one or more groups selected from flourine, chlorine, bromine, iodine, hydroxy, alkyl of 1 to 6 carbon atoms, trifluoromethyl, cyano and amino.
The pharmaceutically acceptable salts are the acid addition salts which can be formed from a compound of the above general formula and a pharmaceutically acceptable acid such as phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic, fumaric, acetic, lactic or methanesulfonic acid.
The compounds of this invention contain a chiral center, providing for various steroisomeric forms such as racemic mixtures as well as optical isomers. The individual optical isomers can be prepared directly or by asymmetric or sterospecific synthesis or by conventional separation of optical isomers from the racemic mixture.